Beta amyloid deposition may be one of several key early events in the pathogenesis of Alzheimer's disease (AD) which leads to neuronal degeneration, but the etiology of this process is unknown. In a few families with inherited AD, a single amino acid substitution in the amyloid precursor protein gene (APP) may lead to a subtle alteration in the metabolism of this peptide. AD might also be caused by the release of beta amyloid following head injury. Thus, the etiology of AD is likely to be the result of both genetic and environmental factors. We intend to exploit and extend this view by proposing that the cause of AD may also result from an interaction between genetic and environmental factors. Similarly, the etiology of dementia in Parkinson's disease (PD), although clinically and pathologically similar to AD, is not known. To achieve a concentrated and unique effort we shall: a) amplify existing research on AD and related dementias by incorporating analytic studies of environmental risk factors; b) develop research in genetic epidemiology to examine the interaction between environmental and genetic risk factors; c) initiate studies of the "molecular epidemiology" of AD integrating both molecular biology and epidemiology into a large scale investigation of elderly in Northern Manhattan. Two outstanding young investigators have been identified to develop parallel programs during this proposal. Karen Marder, MD, MPH, will identify and measure the relationship between environmental and genetic risk factors in the causal pathway of dementia in PD with a case- control study building on her work showing an increased risk of AD in the first-degree relatives of demented patients with PD. Benjamin Tycko, MD, PhD, will use single strand conformation polymorphism to screen for mutations in a larger portion of the APP gene than has been previously examined in controls, patients with AD, PD and Down's syndrome. Mutations in exons might imply an abnormal production of amyloid, whereas mutations in promoter regions could indicate abnormal expression. He will also explore somatic genetic events, such as post-zygotic chromosomal nondisjunction that could lead to low level mosaic trisomy 21 resulting in "genetic basis" for sporadic AD. The intent of this proposal is to lead new and developing scientists into research for AD. The intent of this proposal is to lead new and developing scientists into research for AD. The future dictates that basic and clinical scientists must collaborate in approaching AD, we describe here a series of studies in molecular epidemiology and gene-environment interaction that should achieve that goal.